Several lines of evidence suggest that aspects of drug abuse and addiction may be understood as drug-induced neural plasticity {Nestler, 1993 #3645}. Immediate early genes (IEGs) are believed to play a role in mediating stimulus-induced neural plasticity and several laboratories have examined the IEG response induced by cocaine to identify changes in gene expression that may underlie the long-term neurochemical and behavioral effects of cocaine. Our laboratory has been successful in implementing a differential screening strategy to identify novel, brain IEGs and we have focused on a subset of these genes that are dynamically regulated by cocaine. One of these novel IEGs, termed clone 62, is the focus of this proposal. Preliminary studies indicate that 62 protein is a cytosolic protein that modifies neuronal structure and growth properties. Unlike other IEGs which encode transcription factors, 62 is a member of a newly recognized class of "effector" IEGs that can directly modify cellular function. 62 mRNA is rapidly and transiently induced in neurons of the striatum by cocaine and by NMDA-dependent synaptic mechanisms in association with long-term potentiation in the hippocampus, suggesting a role in several forms of neural plasticity. Northern analyses indicate that 62 mRNA expression is restricted to brain where it is enriched in telencephalic structures. Our preliminary assays of 62 function indicate that 62 blocks growth factor-induced cytodifferentiation of PC12 cells and modifies growth properties of NIH3T3 fibroblasts. Using the yeast 2- hybrid system, we have identified proteins that physically interact with 62 and that are candidates to function with 62 in the cell. One of these is the metabotropic glutamate receptor, mGluR5. The major focus of this proposal is to continue our analysis of the cellular and biochemical functions of 62 and its regulation by acute and chronic administration of cocaine. Experiments in AIM 1 will focus on identifying proteins that interact with 62 and that are likely physiological partners. Candidate proteins include mGluR5 and a novel cytoskeletal protein. AIM 2 will develop cellular assays of 62 function and examine the hypothesis that 62 modifies neuronal cytodifferentiation. In AIM 3 will examine the dynamics and cellular localization of 62 expression in the forebrain and its regulation by acute and chronic administration of cocaine. These studies will provide basic information regarding the molecular mechanisms underlying neurochemical and cellular effects of cocaine.